The present invention discloses an improved process for the preparation of 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I) 
by the condensation of 7-amino cephalosporanic acid (7-ACA) represented by formula (II) with furyl-2-carbonylthiol represented by formula (III) using borontrifluoride or its complex as condensing agent. 
Ceftiofur is the generic name given to compound of formula (IV) 
Ceftiofur acid, its alkali metal, alkaline earth metal and amines salts were reported for the first time in U.S. Pat. No. 4,464,367. The ceftiofur is a condensation product of 7-ACA with furyl-2-carbonylthiol and 2-(2-aminothiazol-4-yl)2-methoxyimino)acetic acid at 3 and 7 position respectively. 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I) is the key intermediate which decides the quality and overall yield of the process for making the ceftiofur.
To our surprise there are very few methods reported in the literature for the synthesis of 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid of the formula (I). The first report for the synthesis of this intermediate appeared in the U.S. Pat. No. 4,464,367 where the method used for the condensation was taken from a reference from the Journal of Antibiotics 27, 573-8, (1974). These references are about the condensation carried out at a pH of 6.4 using phosphate buffer. The reaction time is very long by following this method and 47% yield is reported for the reaction. These limitations make the process unfavorable for the commercial exploitation.
Another method was disclosed in WO patent 87/01117, which is also merely an extension of the earlier mentioned patent. The condensation was affected by reaction of sodium thiofuroate and 7-ACA at a temperature of 65xc2x0 C. in aqueous medium at an pH of 6.4. Cephalosporins are known to decompose at high temperature and moreover using the process using this process, the reaction is not completed and yields are also very poor (about 45% and in addition the reaction takes longer time, for example, even after several hours the reaction is incomplete).
Looking at all these problems, a method for the condensation under non-aqueous was reported in U.S. Pat. No. 5,387,679 where condensation of 7-ACA with heterocyclic thiols in the presence of complex of borontrifluoride with dialkyl carbonate was carried out to provide intermediates which are used in the synthesis of cephalosporin antibiotics. When this method was applied for the condensation of 7-ACA and furyl-2-carbonylthiol the reaction mixture was associated with several impurities which could not be separated even during the final purification step. Later on, after several experimentations we found that the stability of furyl-2-carbonylthiol in its solid form is not good, since furyl-2-carbonylthiol belongs to the class of heterocyclic thioacids and not heterocyclic thiol. The behaviour of the reaction is not similar for the thioacids as it was for thiols thereby disallowing the conditions of the U.S. Pat. No. 5,387,679 to be used in the present invention.
In order to overcome the problem, the applicant provides for the first time an improved process for condensing 7-ACA with furyl-2-carbonylthiol which is generated and used in situ in the presence of borontrifluoride in a gaseous state or its solution in an organic solvent to obtain compound of formula (I). This process gives desired compound of formula (I) in excellent yield (90-95%) and high purity 98-99%).
The primary object of the invention is to provide an improved and commercially viable process for preparing 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid of formula (I) as an intermediate for ceftiofur.
Another object of the invention is to use furyl-2-carbonylthiol in situ without isolating it.
Yet another objective of this invention is to provide a process, this will give high yield and excellent purity of the product.
Still another object of the invention is to provide the use of boron trifluoride in gaseous state or its solution in an organic solvent or boron trifluoride complex for carrying out the condensation reaction at low temperature, which is convenient for commercial production.
Accordingly, the present invention provides the process for preparation of 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid (I) by the condensation of 7-aminocephalosporanic acid (II) with furyl-2-carbonylthiol (III) in the presence of borontrifluoride or its complex, in an organic solvent or mixture of solvents at 0-50xc2x0 C.
The sequence of the reaction is shown below: 